FOR THE PAST 25 years, Linda Watkins, distinguished professor in the department of psychology and neuroscience at the University of Colorado, Boulder, has been exploring what causes chronic pain. She believes that signals from glial cells, part of the body’s immune system, are instrumental. These cells are best known as housekeepers of the body, clearing out dying and dead cells from the sites of viral and bacterial infections and injured tissues—very boring tasks, say Watkins. But things got more interesting when, in the early 1990s, she discovered that glia also communicate with nerve cells and ramp up the pain signals they carry. “When Watkins first began talking about how glia drive pain, almost no one believed her; now almost everyone does,” say David Thomas, a program officer at the National Institute on Drug Abuse.

When you get the flu, it’s glial cells—which make up 85% of the cells in the brain—that release pro-inflammatory cytokines to fight the virus. Although the resulting inflammation can be painful, it keeps the illness in check, and the response generally subsides once you recover. But in some cases, for example when glia are confronted with the chronic inflammation of arthritis or nerve damage from diabetes, they remain agitated. They release more and more neurotoxic chemicals, and those, in turn, excite neurons, creating a feedback loop: overstimulated glia cause more and more inflammation, which activates stronger pain signals from neurons and amplifies pain.

Understanding the underlying causes of pain could lead to better therapies for relieving it, a quest that Watkins and many other researchers are now engaged in. The principal drugs that physicians today can offer to people with severe, persistent pain are opioids, which include both those derived from opium and others synthetically reproduced to have similar effects. In addition to morphine, still widely used in hospitals, there are hydrocodone (Vicodin), oxycodone (OxyContin), methadone and fentanyl. “Opioids are our most effective analgesic, and they’re cheap,” says pain researcher Andrew Coop, professor and associate dean at the University of Maryland School of Pharmacy.

Cheap and effective, however, doesn’t equal safe, and for 11 million or so Americans who take opioids for chronic pain, side effects include constipation, nausea, sleepiness, confusion and slowed breathing, which can result in death. Some people also get opioid-induced hyperalgesia—opioids ramp up their pain instead of knocking it down. “Pain is such an important warning system that the body may try to get that pain sensation back,” says Gregory Terman, professor of anesthesiology and pain medicine at the University of Washington and past president of the American Pain Society. “Pain signals can become even stronger,” and the opioids lose their ability to mute them.”

There’s also the problem that lots and lots of people—5% of the U.S. population, by one estimate—use opioids to get high. They steal the drugs, crib them from friends and family, and trick doctors into writing prescriptions. That often leads to addiction—affecting some 2.5 million U.S. adults in 2014—and overdoses have become increasingly common, taking 19,000 U.S. lives that same year.

Alternative strategies—from physical therapy and behavioral interventions to psychological counseling and surgery—can mitigate chronic pain without the dangers of opioids. But many clinicians don’t have the time or expertise to steer their patients in those other directions. “Primary care providers spend one minute on average asking about pain during a typical 11-minute appointment,” says Thomas. “That isn’t enough time to come up with a treatment plan that might be effective.” Opioids are the default option.


What’s needed is a better drug that can relieve pain as well as or better than opioids do but without being as addictive or prone to abuse. And several may be on the way. Beyond Watkins’ work to tamp down hyperactive immune system cells that help fuel chronic pain, other researchers are developing novel medications that selectively target the nerve and brain structures that opioids use, but only to spur analgesic effects. Other scientists believe that cannabinoids—related to marijuana but with fewer undesirable effects—can work by themselves or with low doses of opioids to provide safer pain relief.

MUCH OF THE RESEARCH into opioid alternatives starts by investigating how opioids operate—and how they can misfire. One big question involves why the drugs’ effectiveness in treating acute pain often wanes when patients take opioids for longer periods. Watkins’ work with glia, for example, has indicated that long-term opioid therapy may have an effect similar to that of chronic inflammation, causing glial cells to release an excess of cytokines that actually reduce the drug’s effectiveness in blocking pain. Indeed, in rats, she showed that giving morphine after nerve injury doubled the duration of neuropathic pain in the animals. This suggests that opioids may do more to sustain chronic pain than to relieve it. Now, she is studying whether the stress of injury or surgery may also prime glia to remain activated. That could explain why some people who suffer acute pain later develop chronic pain that won’t go away and is more difficult to treat.

Watkins believes that calming down glia and immune cells at inflammation sites could help alleviate pain from inflammatory conditions such as osteoarthritis as well as neuropathic pain caused by nerve injury from disease. Xalud Therapeutics, a company she co-founded, has developed a therapy that boosts the production of interleukin-10, a potent anti-inflammatory cytokine. A DNA molecule carrying a gene that produces the interleukin-10 protein is injected into the fluid surrounding the spinal cord or into the inflamed arthritic joint. Unlike viral gene therapy, which permanently changes a person’s genetic makeup, this approach is temporary and increases production of interleukin-10 only at the site of the injection. Having additional interleukin-10 there can help counteract raging pro-inflammatory cytokines.

This gene therapy drug from Xalud Therapeutics (XT-150) has been tested in pet dogs that have chronic pain—osteoarthritis, dysplasia, neuropathic pain and disk degeneration—with remarkable results. After one injection, the effects of which lasted three months, dogs who could barely walk and were about to be euthanized to relieve their suffering “got their doghood back,” says Watkins. XT-150 has also been tested in horses with surgically induced osteoarthritis, and it improved their range of motion and reduced the number of lesions in their joints. Because of successes in these species, rather than merely in rats, Watkins is hopeful that the therapy will be successful in people too. Clinical trials should begin soon.

OTHER WORK TO FIND alternatives to opioids focuses on how the drugs mimic the effects of opioids that the human body produces itself to help protect it in times of stress. “If you’re running from a bear, you don’t want to feel the stones under your feet hurting you, so stress can activate systems that inhibit pain,” says Terman. Those naturally produced opioids, and the opioid drugs that imitate them, inhibit pain by acting on three kinds of opioid receptors—mu, kappa and delta—that are found on the outside of nerve cells in the brain, spinal cord, digestive tract and elsewhere.

But it’s the mu receptor that is primarily responsible for opioids’ analgesic effects, and drugs that fit it snugly launch a cascade of chemical changes in nerve cells that slow down the transmission of pain messages to the spinal cord and the brain. The brain may further modulate the pain signal by activating the “descending pain control system,” made up of bundles of nerve fibers that travel from brain to spinal cord to decrease the pain signal. Opioids work to activate this pathway via the mu receptor, and decrease the signal coming in from the painful site. At their best, opioids may reduce pain by as much as 40%.

The kappa receptors are less involved with addiction than mu, though kappa-based drugs can cause emotional distress and hallucinations. Delta-based drugs are not strong enough for severe pain, but are thought to enhance mood. Since the discovery of the three receptors in the 1970s, scientists have experimented with compounds that turn the receptors on and off in different combinations. They have sought to identify which cellular processes produce pain relief and which are responsible for opioids’ side effects, with the goal of finding compounds that relieve pain at a lower dose, for a longer time, and without increasing tolerance.

To help in this research, researchers bred mice that lacked one or more of the opioid receptors. It turned out that those without a delta receptor that were given morphine didn’t develop tolerance or dependence on the drug. And while it wasn’t possible to do away with the delta receptor in humans, it was hoped that blocking its action might help in similar ways.

Now, after more than 15 years of research, Maryland’s Andrew Coop has patented a compound—UMB 425—that binds to the mu receptor to deliver pain relief, while simultaneously blocking the delta receptor. To test its effectiveness in regular mice that have all of their opioid receptors, Coop injected either a large dose of morphine or UMB 425 twice a day for five days. By day three, the mice on morphine felt pain when briefly exposed to high heat, indicating that they had developed tolerance to the drug. But that didn’t happen to the mice on UMB 425, apparently because they continued to enjoy the analgesic effects of the new drug. Moreover, unpublished data shows that mice on UMB 425 also avoided withdrawal symptoms when the drug was taken away. Next, Coop hopes to test the drug in larger mammals.


A STUDY PUBLISHED LAST summer in Nature described another opioid-like drug candidate—PZM21. In 2012, a co-author of the study, Nobel Laureate Brian Kobilka, determined the physical structure of the mu receptor, and with its exact size and shape in hand, an international team of scientists sought to create a compound that would fit it, conferring analgesia in a way that would trigger fewer side effects than opioids.

Using computer simulations called molecular docking, team members screened more than 3 million molecules to find some 2,500 that fit the mu receptor like a perfectly cut key in a lock. But Brian Shoichet, co-senior author on the Nature paper and professor in the department of pharmaceutical chemistry at the University of California, San Francisco, says that they had another requirement, too, which was met by only a tiny subset of those molecules.

The researchers wanted to activate one typical response—G protein signaling—while not activating something called the beta-arrestin2 pathway. Conventional opioids activate both pathways, which causes constipation and slowed breathing and may induce an increased tolerance of drugs such as morphine.

After much winnowing and retesting, one molecule stood out. The scientists then added two atoms that made its affinity for the mu receptor 40 times stronger. The final chemical, PZM21, was tested in mouse experiments and proved more potent than morphine, lasted longer and didn’t produce the constipation and depressed respiration that morphine does. Nor did mice seek out PZM21 in the way that they craved morphine or act frenetic when they got it—signs of addiction, Shoichet says.

Meanwhile, a drug that works much the same way—by blocking the beta-arrestin2 pathway while activating the G protein pathway at the mu opioid receptor—is currently in the final stages of human clinical trials. In an earlier round of testing, 200 people who had undergone abdominoplasty—a tummy-tuck surgery that entails a foot-long incision—were randomly assigned to receive the new drug—oliceridine—or morphine or a placebo following surgery. In that trial, oliceridine provided at least as much pain relief as morphine did, and patients who received the new drug suffered significantly less nausea, vomiting and hypoventilation (a measure of slowed breathing) than patients on morphine.

Oliceridine received “breakthrough therapy” status from the FDA, a designation aimed to help speed development of medicines that have shown evidence of clinical promise in treating serious or life-threatening conditions. When a drugmaker applies for and gets this status, the FDA expedites review of the therapy to get it to market faster. Oliceridine may be reviewed by the agency on an accelerated schedule if a final phase of clinical testing—including randomized controlled trials of some 750 hospitalized patients who’ve had painful surgery—is successful, according to Trevena, the company that developed the drug.

One possible application for oliceridine is as an alternative to opioids such as morphine or fentanyl for treating hospitalized patients who have acute pain after surgery or from cancer or a condition such as kidney stones. Because high doses of opioids have the potential to cause respiratory arrest or other dangerous side effects, doctors may hesitate to give patients as much of the drugs as they need to relieve their pain, says David Soergel, chief medical officer at Trevena. Oliceradine might help mitigate such concerns.

YET ANOTHER POSSIBLE ALTERNATIVE to opioids involves the many chemicals unique to cannabis, collectively known as cannabinoids. Medical marijuana, for example, may help reduce the chronic neuropathic pain that is often caused by chemotherapy while also relieving nausea and vomiting. And an overdose of marijuana is never fatal because the drug doesn’t slow heart rate and breathing as opioids do. But delta-9-tetrahydrocannabinol (THC), the main psychoactive ingredient in cannabis, makes people high and eventually causes physical dependence and tolerance to its pain-relieving properties. Those unwanted side effects occur when THC binds to a receptor in the brain called cannabinoid CB1.


Pain researcher Andrea Hohmann, professor and a chair of neuroscience at Indiana University, Bloomington, is attempting to target a different cannabinoid receptor—CB2—to get pain suppression without the high. In rats that developed neuropathic pain from chemotherapy, a CB2 agonist (a molecule that binds strongly to the CB2 receptor and activates it) continued to relieve pain despite repeated dosing. In fact, in a separate study, the CB2 agonist remained effective when it was continuously infused over four weeks. And the relief continued for several weeks after the drug was stopped. “The pain does come back eventually, but we’re giving the rats extremely low doses and are not seeing unwanted side effects,” says Hohmann.

In fact, mice that received repeated doses of THC developed complete tolerance to the drug and became impervious to its therapeutic effects. The CB2 agonist also doesn’t appear to be addictive; rats who had received it didn’t seek out another infusion unless they were in pain. Rats that have access to addictive substances such as cocaine, however, will continually press a lever to get more of the drug, even when it has been replaced by saline.

Now Hohmann is trying to determine what cell activity is responsible for the therapeutic properties of CB2 agonists. She envisions that chronic pain patients may benefit from the combined pain relief of a CB2 agonist and a low-dose opioid. “If you can reduce the amount of opioids needed to suppress pain, you may be able to avoid unwanted side effects,” she says.

Of course, cannabinoids or other new pain drugs may face practical obstacles. Jianren Mao, chief of the Division of Pain Medicine at Massachusetts General Hospital, remembers the optimism a few years ago about “tamper-resistant” opioid drugs—new formulations of current medications that are supposed to curtail their being misused for getting high through being crushed, snorted or injected. “Few of those drugs have become extensively used in practice for a number of reasons, including their higher cost, and many are still not covered by insurers,” he says. Some users have also been able to bypass the safer formulations to obtain highs from the drugs.

Even if new classes of painkillers gain FDA approval, they will exist in a landscape shaped by opioids. “Opium has been around since the beginning of recorded history, and we’ll likely always have opioids because they work so intimately on pain pathways,” says Gary Brenner, assistant professor in anesthesia and director of the MGH Pain Medicine Fellowship  “We just need to do a better job eliminating side effects and building a bigger armamentarium of treatments—so that we can rely less on opioids.”